Production method of 2,6-dihalopurine

ABSTRACT

By reacting the compound of the formula [Ia] or [Ib] with halosilane compound and an agent for diazo reaction, 2,6-dihaliopurine of the formula [II] can be produced conveniently in a high yield and can be easily isolated, wherein each symbol is as defined in the specification.

TECHNICAL FIELD

The present invention relates to a production method of2,6-dihalopurine. More particularly, the present invention relates to aproduction method of 2,6-dihalopurine, which is useful as a startingmaterial for a nucleoside analog and the like useful as a pharmaceuticalproduct.

BACKGROUND ART

There are various production methods of 2,6-dihalopurine of the formula

wherein X¹ and X² are the same or different and each is halogen atom.Known methods include, for example, (A) a method comprising chlorinationof xanthine with pyrophosphoryl chloride (Journal of American ChemicalSociety, 78, 3508-10 (1956)), (B) a method comprising chlorination ofN-oxide of hipoxanthine or 6-chloropurine with phosphorus oxychloride(JP-B-45-11508, U.S. Pat. No. 3,314,938), (C) a production methodcomprising 4 steps using barbituric acid derivative as a startingmaterial (Journal of Organic Chemistry, 19, 930 (1954), Journal ofAmerican Chemical Society, 80, 404-8 (1958)), (D) a production methodcomprising cyclization of 2,4-dichloro-5,6-diaminopyrimidine (U.S. Pat.No. 2,844,576) and the like.

However, the aforementioned method (A) is associated with defects inthat it requires preparation of pyrophosphoryl chloride as achlorinating agent from phosphorus oxychloride by a complicated method,as well as a high reaction temperature of 165° C., the use of acorrosion resistant reaction container for the reaction and a longreaction time of about 19 hours. The aforementioned methods (A)-(D) areall defective in that they require long steps and complicatedmanipulations.

In addition, use of a method using a starting material, wherein the9-position of the purine ring is alkylated, has been considered, and thefollowing reaction was reported in, for example, J. Chem. Soc., PerkinTrans. 1, 1999, 3469-3475

In this reaction, chlorotrimethylsilane and isoamyl nitrite were used indichloromethane to give dichloropurine derivative, wherein the9-position of the purine ring was alkylated, in a yield of 61%.

Furthermore, J. Chem. Soc., Perkin Trans. 1, 1989, 2207-2213 reports thefollowing reaction

In this reaction, isoamyl nitrite was used in carbon tetrachloride togive dichloropurine derivative, wherein the 9-position of the purinering was alkylated, in a low yield of 40%. To obtain the objective2,6-dihalopurine, wherein the 9-position is unsubstituted, the alkylgroup at the 9-position needs to be removed. However, there is no knownmethod for this end, and conversion to 2,6-dihalopurine, wherein the9-position is unsubstituted, is difficult. Thus, this method is not apreferable one.

In view of the above, the development of a convenient production methodto afford the objective 2,6-dihalopurine in a high yield is desired,which allows easy isolation thereof.

It is therefore an object of the present invention to provide a methodfor conveniently producing the objective 2,6-dihalopurine in a highyield, which allows easy isolation thereof.

DISCLOSURE OF THE INVENTION

As a result of the intensive studies in an attempt to achieve theabove-mentioned object, it has been found that, by reacting a compoundof the formula [Ia] or [Ib]

wherein X¹ is a halogen atom and R is a hydrogen atom or acyl group(hereinafter both to be abbreviated as compound [I] unless particularlyspecified) with halosilane compound and an agent for diazo reaction,2,6-dihalopurine of the formula [II]

wherein X¹ and X² are the same or different and each is a halogen atom(hereinafter to be abbreviated as 2,6-dihalopurine) can be producedconveniently in a high yield, and that the objective product can beisolated easily.

Accordingly, the present invention provides the following.

-   (1) A production method of 2,6-dihalopurine, which comprises    reacting compound [I] with a halosilane compound and an agent for    diazo reaction.-   (2) The production method of the above-mentioned (1), wherein the    agent for diazo reaction is a nitrite ester.-   (3) The production method of the above-mentioned (2), wherein the    nitrite ester is isoamyl nitrite.-   (4) The production method of the above-mentioned (1), wherein the    reaction is carried out in the presence of a quarternary ammonium    salt.-   (5) The production method of the above-mentioned (4), wherein the    quarternary ammonium salt is tetraethylammonium chloride or    benzyltriethylammonium chloride.-   (6) The production method of the above-mentioned (1), wherein R is    an acyl group.-   (7) The production method of the above-mentioned (6), wherein the    acyl group for R is acetyl group.-   (8) The production method of the above-mentioned (1), wherein the    halosilane compound is chlorotrimethylsilane or    dichlorodimethylsilane.-   (9) The production method of the above-mentioned (1), wherein the    halosilane compound is bromotrimethylsilane.-   (10) The production method of the above-mentioned (1), wherein,    after introducing an acyl group into the 9-position or the    7-position of compound [I], wherein R is a hydrogen atom, the    obtained compound [I], wherein R is acyl group, is reacted with    halosilane compound and the agent for diazo reaction.

DETAILED DESCRIPTION OF THE INVENTION

The 2,6-dihalopurine of the present invention encompasses tautomer.

The “acyl group” for R is a group represented by —C(═O)—R′ wherein R′means, for example, a hydrocarbon group. The hydrocarbon group includeslinear, branched chain or cyclic ones, which may be aliphatic oraromatic. Preferable acyl group includes alkylcarbonyl group having 2 to6 carbon atoms (e.g., acetyl group, propionyl group, butanoyl group andthe like), benzoyl group and the like. From the aspect of improvement inreactivity and economical aspect, acetyl group is particularlypreferable. Since the acetyl group can be characteristically releasedeasily by hydrolysis, compound [I], wherein R is acetyl group, can beeasily converted to 2,6-dihalopurine.

The “halogen atom” for X¹ and X² is fluorine atom, chlorine atom,bromine atom or iodine atom, and X¹ and X² may be the same or differenthalogen atom.

The present invention is explained in detail in the following.

By a method comprising step for reacting compound [I] with halosilanecompound and an agent for diazo reaction, 2,6-dihalopurine can beproduced conveniently in a high yield, and the obtained 2,6-dihalopurinecan be easily isolated. The R in compound [I] is preferably an acylgroup, particularly preferably an acetyl group from the reactivity andreleasability. In addition, this reaction in the presence of a phasetransfer catalyst preferably accelerates the reaction rate. As the phasetransfer catalyst in the present invention, for example, quarternaryammonium salt, crown ether (e.g., 12-crown-4, 15-crown-5, 18-crown-6etc.), alkyl sulfate (e.g., sodium octylsulfate etc.), alkyl sulfonate(e.g., sodium octylsulfonate etc.) and the like can be included, withpreference given to quarternary ammonium salt. The amount of the phasetransfer catalyst to be used is a 0.005-0.2 molar amount, preferably0.01-0.1 molar amount, per 1 mol of compound [I].

The “quarternary ammonium salt” in the present invention is notparticularly limited, and, for example, tetraethylammonium chloride,benzyltriethylammonium chloride, trioctylmethylammonium chloride,benzyltrimethylammonium chloride and the like can be used, withpreference given to tetraethylammonium chloride andbenzyltriethylammonium chloride. When a quarternary ammonium salt isused, the use of a catalyst amount of, for example, 0.01-1 mol,preferably 0.05-0.1 mol, per 1 mol of compound [I] is sufficient.

In the halosilane compound to be used in the present invention, at leastone halogen atom is bonded to silicon atom, or alkyl group may be bondedbesides the halogen atom. Examples thereof include trialkylhalosilane,dialkyldihalosilane, monoalkyltrihalosilane and tetrahalosilane. Thealkyl group here is a linear or branched chain alkyl group having 1 to4, preferably 1 or 2, carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Thehalogen atom here includes fluorine atom, chlorine atom, bromine atomand iodine atom.

Specific examples of the halosilane compound includechlorotrimethylsilane, dichlorodimethylsilane, trichloromethylsilane,tetrachlorosilane, bromotrimethylsilane and the like. Preferred arechlorotrimethylsilane, dichlorodimethylsilane and bromotrimethylsilane,and particularly preferred are chlorotrimethylsilane anddichlorodimethylsilane. The halosilane compound can be also used as areaction solvent. The amount of use thereof is 1.5-30 mol, preferably8-20 mol, per 1 mol of compound [I]. It is needless to say, when anorganic solvent other than halosilane compound is used as a reactionsolvent, the amount of halosilane compound to be used can be reducedfrom the above-mentioned range. The amount of halosilane compound to beused is 1-10 mol, preferably 1.5-6 mol, per 1 mol of compound [I].

As the agent for diazo reaction in the present invention, for example,nitrite ester, nitrosyl chloride, nitrosyl sulfate, nitrogen oxide,nitrite salt (e.g., sodium nitrite, potassium nitrite and the like) andthe like can be used, with preference given to nitrite ester. As thenitrite ester, for example, C₁₋₅ alkyl nitrite (e.g., methyl nitrite,ethyl nitrite, propyl nitrite, isobutyl nitrite, tert-butyl nitrite,isoamyl nitrite and the like) and the like. Of these, isoamyl nitrite ispreferable. The amount of the agent for diazo reaction to be used is 1-3mol, preferably 1.1-1.5 mol, per 1 mol of compound [I].

The reaction of the present invention can be carried out in an organicsolvent, and the organic solvent to be used is not particularly limited.From the aspects of reaction rate and suppression of by-product,hydrocarbon solvents such as hexane, heptane and the like, halogenatedsolvents such as monochlorobenzene, dichlorobenzene and the like, andtetrahydrofuran are preferable. Of these, the hydrocarbon solvents suchas hexane, heptane and the like, or halogenated solvents such asmonochlorobenzene, dichlorobenzene and the like are more preferable. Theamount of the organic solvent to be used is 1-100 ml, preferably 2-10ml, per 1 g of compound [I].

The reaction of compound [I] with halosilane compound and an agent fordiazo reaction completes at generally 0-60° C., preferably 20-60° C.,for generally 5-20 hr.

When R is acyl group, 2,6-dihalopurine can be obtained by adjusting thepH of the reaction mixture to 2-5, preferably 4-5, after the completionof the reaction. As a method for adjusting the pH of the reactionmixture, for example, a method comprising addition of an aqueous alkalisolution (e.g., aqueous sodium hydroxide solution etc.) to the reactionmixture, a method comprising addition of an aqueous alkali solution tothe reaction mixture and addition of an aqueous acidic solution (e.g.,hydrochloric acid etc.) and the like can be mentioned.

The obtained 2,6-dihalopurine can be isolated and purified by aconventional method. For example, the obtained reaction mixture iscooled, and the precipitated crystals are collected by filtration anddried. The collected crystals are washed or recrystallized to givecrystals having a higher purity.

The obtained 2,6-dihalopurine can be converted to a nucleoside analoguseful as a pharmaceutical product according to the method described in,for example, EP656,778.

The compound [I] as the starting material can be obtained by thefollowing method.

The compound [I] wherein R is hydrogen atom is commercially availableand a commercially available one can be used for the reaction. It isneedless to say that one produced by a known method (e.g., EP543,095etc.) can be used.

The compound [I] wherein R is acyl group can be obtained by, forexample, introducing an acyl group into the 7-position or 9-position ofcompound [I], wherein R is hydrogen atom, according to a conventionalmethod. An acyl group can be generally introduced in the same manner asthe protection of amino group with acyl group. For example, compound [I]wherein R is hydrogen atom is reacted with R′—C(═O)OH wherein R′ is ahydrocarbon group defined above, or a reactive derivative thereof (e.g.,ester, acid halide, acid anhydride etc.) to give compound [I] wherein Ris acyl group.

The introduction of acyl group is explained in the following.

When compound [I] wherein R is hydrogen atom is reacted with acidhalide, a base is preferably co-used from the aspect of improvedreactivity and economical aspect. Examples of the base include organicbase (e.g., triethylamine and the like), and inorganic base (e.g.,carbonate, hydrogencarbonate and the like). The amount of the base to beused is 1-3 mol, preferably 1.1-2 mol, per 1 mol of compound [I] whereinR is hydrogen atom.

The amount of R′—C(═O)OH and a reactive derivative thereof to be usedfor introduction of acyl group is generally 1-3 mol, preferably 1.1-2mol, per 1 mol of compound [I] wherein R is hydrogen atom.

The acyl group can be introduced without a solvent or in an organicsolvent, and the introduction without a solvent is economical andconvenient because the solvent does not need to be evaporated. When itis introduced in an organic solvent, as the organic solvent, the samesolvent as the organic solvent used for the above-mentioned reaction ofcompound [I] with halosilane compound and an agent for diazo reactioncan be used. Other than that, N,N-dimethylacetamide, tetrahydrofuran,ethyl acetate and the like can be used. From the aspect of reactivity,the use of N,N-dimethylacetamide is preferable. The use of the samesolvent as the organic solvent used for the above-mentioned reaction ofcompound [I] with halosilane compound and an agent for diazo reaction ispreferable, because the solvent does not need to be evaporated and,after the formation of compound [I], compound [I] can be reacted withhalosilane compound and an agent for diazo reaction in one pot withoutisolation. When the reaction is carried out in an organic solvent, theamount of the organic solvent to be used is 1-20 parts by weight,preferably 2-5 parts by weight, per 1 part by weight of compound [I]wherein R is hydrogen atom.

While the introduction of acyl group varies depending on the reactionconditions and the like, it is completed at generally 1-100° C.,preferably 40-60° C., for generally 1 hr-10 hr, preferably 3 hr-6 hr.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples. The present invention is not limited by theseexamples.

Example 1

(1) Synthesis of 9-acetyl-2-amino-6-chloropurine

2-Amino-6-chloropurine (150 g, 0.89 mol) and acetic anhydride (108 g,1.06 mol) were added to N,N-dimethylacetamide (350 ml), and the mixturewas heated to 50-60° C. and stirred for 4 hr. The reaction mixture wascooled and filtrated. The obtained crystals were washed with isopropanol(400 ml) and dried at 80° C. under reduced pressure to give9-acetyl-2-amino-6-chloropurine as a pale-yellow powder (187 g, yield99.0%).

¹H-NMR (400 MHz, DMSO-d₆) δ=2.83(s,3H), 7.26(brs,2H), 8.55(s,1H).

¹³C-NMR (100 MHz, DMSO-d₆) δ=24.65, 124.02, 139.73, 150.09, 152.89,160.13, 167.69.

(2) Synthesis of 2,6-dichloropurine

9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol),dichlorodimethylsilane (1.01 g, 7.80 mmol), tetraethylammonium chloride(0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol) were addedto heptane (4 ml), and the mixture was heated to 50-60° C. and stirredfor 14 hr. After the completion of the reaction, the mixture wasfiltrated. The obtained crystals were diluted with water (4.0 ml), andthe mixture was adjusted to pH 4-5 with a 2M aqueous sodium hydroxidesolution. After aging under ice-cooling for 1 hr, the mixture wasfiltrated, and the obtained crystals were dried under reduced pressureat 80° C. to give a white powder (0.31 g, yield 73.8%) of2,6-dichloropurine.

melting point: 184-186° C.

¹H-NMR(400 MHz, DMSO-d₆) δ=8.74(s,1H), 14.15(s,1H).

¹³C-NMR(100 MHz, DMSO-d₆) δ=128.35, 147.16, 150.58, 155.93.

Example 2

Synthesis of 2,6-dichloropurine

9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol), tetraethylammoniumchloride (0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol)were added to chlorotrimethylsilane (4.0 g, 36.8 mmol), and the mixturewas heated to 50-60° C. and stirred for 10 hr. After the completion ofthe reaction, the mixture was filtrated. The obtained crystals werediluted with water (4.0 ml), and the mixture was adjusted to pH 4-5 witha 2M aqueous sodium hydroxide solution. After aging under ice-coolingfor 1 hr, the mixture was filtrated, and the obtained crystals weredried under reduced pressure at 80° C. to give 2,6-dichloropurine as awhite powder (0.35 g, yield 78.3%). The properties of the obtainedcompound were the same as in Example 1(2).

Example 3

Synthesis of 2,6-dichloropurine

9-Acetyl-2-amino-6-chloropurine (2.50 g, 11.8 mmol),dichlorodimethylsilane (4.57 g, 35.4 mmol), benzyltriethylammoniumchloride (0.16 g, 0.70 mmol) and isoamyl nitrite (2.07 g, 17.7 mmol)were added to o-dichlorobenzene (10 ml), and the mixture was heated to25-30° C. and stirred for 8 hr. After the completion of the reaction,the mixture was filtrated. The obtained crystals were diluted with water(4.0 ml), and the reaction mixture was added dropwise to 2M aqueoussodium hydroxide solution (20 ml) and partitioned. The aqueous layer wasadjusted to pH 4-5 with 35% hydrochloric acid. After aging underice-cooling for 1 hr, the mixture was filtrated, and the obtainedcrystals were dried under reduced pressure at 80° C. to give2,6-dichloropurine as a white powder (1.62 g, yield 72.6%). Theproperties of the obtained compound were the same as in Example 1(2).

Example 4

Synthesis of 2,6-dichloropurine

2-Amino-6-chloropurine (5.00 g, 29.5 mmol), dichlorodimethylsilane(11.42 g, 88.5 mmol), benzyltriethylammonium chloride (0.40 g, 1.8 mmol)and isoamyl nitrite (5.18 g, 44.2 mmol) were added to heptane (25 ml),and the mixture was heated to 50-60° C. and stirred for 17 hr. After thecompletion of the reaction, the mixture was filtrated. The obtainedcrystals were diluted with water (25 ml) and adjusted to pH 4-5 with a2M aqueous sodium hydroxide solution. After aging under ice-cooling for1 hr, the mixture was filtrated, and the obtained crystals wererecrystallized from methanol. The mixture was dried under reducedpressure at 60° C. to give 2,6-dichloropurine as a white powder (3.68 g,yield 66.1%). The properties of the obtained compound were the same asin Example 1(2).

Example 5

(1) Synthesis of 9-acetyl-2-amino-6-iodopurine

In the same manner as in Example 1 except that 2-amino-6-iodopurine wasused instead of 2-amino-6-chloropurine, the mixture was stirred for 15hr. The reaction mixture was subjected to post-treatment in the samemanner as in Example 1 to give 9-acetyl-2-amino-6-iodopurine as a whitepowder. (yield 94.6%)

¹H-NMR(400 MHz, DMSO-d₆) δ=2.82(s,3H), 7.18(brs,2H), 8.51(s,1H)

³C-NMR(100 MHz, DMSO-d₆) δ=24.80, 124.02, 131.04, 138.82, 149.02,159.88, 167.90

(2) Synthesis of 2-bromo-6-iodopurine

9-Acetyl-2-amino-6-iodopurine (1.44 g, 4.72 mmol), bromotrimethylsilane(2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g, 5.67 mmol) were addedto tetrahydrofuran (5 ml), and the mixture was stirred 20-25° C. for 19hr to give 2-bromo-6-iodopurine.

LC/MS(−c ESI) m/z 323, 325(M⁻¹)

Example 6

Synthesis of 2-bromo-6-chloropurine

9-Acetyl-2-amino-6-chloropurine (1.00 g, 4.72 mmol),bromotrimethylsilane (2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g,5.67 mmol) were added to tetrahydrofuran (5 ml), and the mixture wasstirred at 20-25° C. for 19 hr to give 2-bromo-6-chloropurine.

LC/MS(−c ESI) m/z 231, 233, 235 (M⁻¹)

INDUSTRIAL APPLICABILITY

According to the present invention, the objective 2,6-dihalopurine canbe produced conveniently in a high yield and easily isolated.

This application is based on patent application No. 2002-102456 filed inJapan, the contents of which are hereby incorporated by reference.

1. A production method of 2,6-dihalopurine of the formula [II]

wherein X¹ and X² are the same or different and each is a halogen atom,which comprises reacting a compound of the formula [Ia] or [Ib]

wherein X¹ is a halogen atom and R is a hydrogen atom or acyl group,with a halosilane compound and an agent for diazo reaction.
 2. Theproduction method of claim 1, wherein the agent for diazo reaction is anitrite ester.
 3. The production method of claim 2, wherein the nitriteester is isoamyl nitrite.
 4. The production method of claim 1, whereinthe reaction is carried out in the presence of a quarternary ammoniumsalt.
 5. The production method of claim 4, wherein the quarternaryammonium salt is tetraethylammonium chloride or benzyltriethylammoniumchloride.
 6. The production method of claim 1, wherein R is an acylgroup.
 7. The production method of claim 6, wherein the acyl group for Ris acetyl group.
 8. The production method of claim 1, wherein thehalosilane compound is chlorotrimethylsilane or dichlorodimethylsilane.9. The production method of claim 1, wherein the halosilane compound isbromotrimethylsilane.
 10. The production method of claim 1, wherein,after introducing an acyl group into the 9-position or the 7-position ofcompound of the formula [Ia] or [Ib], wherein R is a hydrogen atom, theobtained compound of the formula [Ia] or [Ib], wherein R is acyl group,is reacted with halosilane compound and the agent for diazo reaction.